2. Academic Validation
  3. Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

  • Nat Genet. 2017 Apr;49(4):537-549. doi: 10.1038/ng.3790.
John J Reynolds 1,  Louise S Bicknell 2,  Paula Carroll 2,  Martin R Higgs 1,  Ranad Shaheen 3,  Jennie E Murray 2,  Dimitrios K Papadopoulos 4,  Andrea Leitch 2,  Olga Murina 2,  Žygimantė Tarnauskaitė 2,  Sarah R Wessel 5,  Anastasia Zlatanou 1,  Audrey Vernet 1,  Alex von Kriegsheim 2,  Rachel M A Mottram 1,  Clare V Logan 2,  Hannah Bye 6,  Yun Li 7,  Alexander Brean 1,  Sateesh Maddirevula 3,  Rachel C Challis 2,  Kassiani Skouloudaki 4,  Agaadir Almoisheer 3,  Hessa S Alsaif 3,  Ariella Amar 6,  Natalie J Prescott 6,  Michael B Bober 8,  Angela Duker 8,  Eissa Faqeih 9,  Mohammed Zain Seidahmed 10,  Saeed Al Tala 11,  Abdulrahman Alswaid 12,  Saleem Ahmed 13 14,  Jumana Yousuf Al-Aama 13 14,  Janine Altmüller 15,  Mohammed Al Balwi 16,  Angela F Brady 17,  Luciana Chessa 18,  Helen Cox 19,  Rita Fischetto 20,  Raoul Heller 21,  Bertram D Henderson 22,  Emma Hobson 23,  Peter Nürnberg 15,  E Ferda Percin 24,  Angela Peron 25 26,  Luigina Spaccini 25,  Alan J Quigley 27,  Seema Thakur 28,  Carol A Wise 29,  Grace Yoon 30 31,  Maha Alnemer 32,  Pavel Tomancak 4,  Gökhan Yigit 7,  A Malcolm R Taylor 1,  Martin A M Reijns 2,  Michael A Simpson 6,  David Cortez 5,  Fowzan S Alkuraya 3,  Christopher G Mathew 6 33,  Andrew P Jackson 2,  Grant S Stewart 1
Affiliations

Affiliations

  • 1 Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
  • 2 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
  • 3 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 4 Max-Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
  • 5 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
  • 6 Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, Guy's Hospital, London, UK.
  • 7 Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
  • 8 Nemours-Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.
  • 9 Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
  • 10 Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.
  • 11 Armed Forces Hospital, SR. P.D. Genetic Unit. Khamis Mushayt, Saudi Arabia.
  • 12 Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
  • 13 Department of Genetic Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.
  • 14 Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia.
  • 15 Cologne Center for Genomics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • 16 Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia.
  • 17 North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Harrow, UK.
  • 18 Department of Clinical and Molecular Medicine, University La Sapienza, Roma, Italy.
  • 19 West Midlands Regional Clinical Genetics Service, Birmingham Women's Hospital, West Midlands, UK.
  • 20 Pediatric Hospital Giovanni XXIII, Bari, Italy.
  • 21 Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
  • 22 Divison of Clinical Genetics, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa.
  • 23 Department of Genetics, Yorkshire Regional Genetic service, Chapel Allerton Hospital, Leeds, UK.
  • 24 Department of Medical Genetics, Gazi University Faculty of Medicine, Besevler Ankara, Turkey.
  • 25 Clinical Genetics Unit, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, V. Buzzi Children's Hospital, Universita' degli Studi di Milano, Milan, Italy.
  • 26 Child Neuropsychiatry Unit-Epilepsy Center, San Paolo University Hospital, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
  • 27 Dept of Radiology, Royal Hospital for Sick Children, Edinburgh, UK.
  • 28 Department of Genetic and Fetal Medicine, Fortis Lafemme, New Delhi, India.
  • 29 Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA.
  • 30 Division of Clinical and Metabolic Genetics, Hospital for Sick Children, University of Toronto, Toronto, Canada.
  • 31 Department of Pediatrics, Division of Neurology, Hospital for Sick Children, University of Toronto, Toronto, Canada.
  • 32 Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 33 Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
PMID: 28191891 DOI: 10.1038/ng.3790
Abstract

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

Figures